Crystel Bonnet - Academia.edu (original) (raw)

Papers by Crystel Bonnet

Proceedings of the National Academy of Sciences of the United States of America, Jun 20, 2023

Functional molecular characterization of the cochlea has mainly been driven by the deciphering of... more Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the search for curative treatments, which are sorely lacking in the hearing field, has become a potentially achievable objective, particularly via cochlear gene and cell therapies. To this end, a complete inventory of cochlear cell types, with an in-depth characterization of their gene expression profiles right up to their final differentiation, is indispensable. We therefore generated a single-cell transcriptomic atlas of the mouse cochlea based on an analysis of more than 120,000 cells on postnatal day 8 (P8), during the prehearing period, P12, corresponding to hearing onset, and P20, when cochlear maturation is almost complete. By combining whole-cell and nuclear transcript analyses with extensive in situ RNA hybridization assays, we characterized the transcriptomic signatures covering nearly all cochlear cell types and developed cell type–specific markers. Three cell types were discovered; two of them contribute to the modiolus which houses the primary auditory neurons and blood vessels, and the third one consists in cells lining the scala vestibuli. The results also shed light on the molecular basis of the tonotopic gradient of the biophysical characteristics of the basilar membrane that critically underlies cochlear passive sound frequency analysis. Finally, overlooked expression of deafness genes in several cochlear cell types was also unveiled. This atlas paves the way for the deciphering of the gene regulatory networks controlling cochlear cell differentiation and maturation, essential for the development of effective targeted treatments.

Datasets associated to the article Phylogenetic analysis of Harmonin Homology Domains. HHD_starti... more Datasets associated to the article Phylogenetic analysis of Harmonin Homology Domains. HHD_starting-profile.hmm -> Profile HMM used to screen the UniprotKB HHD_all-hits_aligned.fa -> All hits aligned Other *.fa correspond to sequences identified for each cluster described in th article

Documenta Ophthalmologica, Jul 2, 2019

Purpose Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vesti... more Purpose Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). Methods A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/ USH3) and correlated with age. Results Visual acuity decreases significantly with age for both USH1 and USH2 (p \ 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04).

Investigative Ophthalmology & Visual Science, Jun 23, 2017

Vision Research, Dec 1, 2012

Purpose of this study was to characterize retinal disease in Usher syndrome using fundus autofluo... more Purpose of this study was to characterize retinal disease in Usher syndrome using fundus autofluorescence and optical coherence tomography. Study included 54 patients (26 male, 28 female) aged 7-70 years. There were 18 (33%) USH1 and 36 (67%) USH2 patients. 49/52 (94%) patients were found to carry at least one mutation in Usher genes. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann visual fields (targets II/1-4 and V/4), microperimetry, fundus autofluorescence imaging and optical coherence tomography. Average age at disease onset (nyctalopia) was significantly lower in USH1 than USH2 patients (average 9 vs. 17 years, respectively; p < 0.01); however no significant differences were found regarding type of autofluorescence patterns, frequency of foveal lesions and CME, rate of disease progression and age at legal blindness. All representative eyes had abnormal fundus autofluorescence of either hyperautofluorescent ring (55%), hyperautofluorescent foveal patch (35%) or foveal atrophy (10%). Disease duration of more than 30 years was associated with a high incidence of abnormal central fundus autofluorescence (patch or atrophy) and visual acuity loss.

Research Square (Research Square), Aug 30, 2021

Deafness has a very variable disease. It may occur as a result of external auditory canal involve... more Deafness has a very variable disease. It may occur as a result of external auditory canal involvement or a de ciency in the sound conduction mechanism (transmission deafness) or impairment of the cochlear, cochlear nerve or central auditory perception. Genetics is the most common cause, as approximately 70% of hearing disorders are of hereditary origin. 1/3 of hereditary deafness is syndromic (associated with other symptoms) and 2/3 are non-syndromic (isolated deafness). At this date, 173 loci of deafness gene have been reported in the literature (69 DFNA, 94 DFNB, 6 X-linked DFN, 2 DFNM, 1 DFNY and 1 AUNA1). For syndromic deafness, approximately 400 syndromes associated with hearing disorders are already described. Thus, the determination of causal mutations is a valuable aid for accurate and early diagnosis. This makes it possible to better guide the management since forms of deafness respond better to the cochlear implant than others. The correct diagnosis also gives an idea of the evolutionary pro le of deafness and whether it is a syndromic deafness requiring special surveillance. In this study, we have examined the genetic causes of sensorineural hearing loss in Moroccan patients through whole exome sequencing (WES) to identify candidate genes for six severely deaf Moroccan families. The results revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB, which are therefore common causes of syndromic and non-syndromic deafness.

Investigative Opthalmology & Visual Science

Background: More than 70 % of the cases of congenital deafness are of genetic origin, of which ap... more Background: More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss. Method: After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling. Results: A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells' stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database. Conclusion: Whole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.

Human Heredity, 2021

Introduction: Auditory neuropathy is a hearing disorder where outer hair cell function within the... more Introduction: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes. Methods: We found a disease-segregating mutation in the X-linked AIFM1 gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1. Results: The impact of the c.1045A>G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance. Discussion/Conclusion: To our knowledge, this is the first study that identifies a mutation in the AIFM1 gene in Moroccan patients suffering from X-linked auditory neuropathy.

Proceedings of the National Academy of Sciences, 2020

Significance Presbycusis, or age-related hearing loss, is a major public health issue and the pri... more Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.

BMC Cancer

Background and study aim Carrying a pathogenic BRCA1/2 variant increases greatly young women’s ri... more Background and study aim Carrying a pathogenic BRCA1/2 variant increases greatly young women’s risk of developing breast cancer (BC). This study aimed to provide the first genetic data on BC in Mauritania. Methods Using NGS based screening; we searched for BRCA1/2 variants in DNA samples from 137 patients diagnosed for hereditary BC. Results We identified 16 pathogenic or likely pathogenic (PV) variants carried by 38 patients. Two predominant BRCA1 PV variants were found: c.815_824dup and c.4986 + 6 T > C in 13 and 7 patients, respectively. Interestingly, three novels BRCA1/2 predicted pathogenic variants have also been detected. Notably, no specific distribution of BRCA1/2 variants was observed regarding triple negative breast cancer (TNBC) or patient gender status. Conclusions In this first genetic profiling of BC in Mauritania, we identified a substantial number of BRCA1/2 pathogenic variants. This finding could be important in the future diagnosis and prevention policy of her...

European Archives of Oto-Rhino-Laryngology

Frontiers in Aging Neuroscience, 2021

The decline of speech intelligibility in presbycusis can be regarded as resulting from the combin... more The decline of speech intelligibility in presbycusis can be regarded as resulting from the combined contribution of two main groups of factors: (1) audibility-related factors and (2) age-related factors. In particular, there is now an abundant scientific literature on the crucial role of suprathreshold auditory abilities and cognitive functions, which have been found to decline with age even in the absence of audiometric hearing loss. However, researchers investigating the direct effect of aging in presbycusis have to deal with the methodological issue that age and peripheral hearing loss covary to a large extent. In the present study, we analyzed a dataset of consonant-identification scores measured in quiet and in noise for a large cohort (n = 459, age = 42–92) of hearing-impaired (HI) and normal-hearing (NH) listeners. HI listeners were provided with a frequency-dependent amplification adjusted to their audiometric profile. Their scores in the two conditions were predicted from t...

BMC Bioinformatics, 2021

Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 resid... more Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein–protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. Results Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic H...

International Journal of Molecular Sciences, 2021

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dy... more The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, althoug...

Investigative Ophthalmology & Visual Science, 2006